Promising bioactivity of curcumin derivatives against malaria: in silico, in vitro and ITC studies

Curcumin, a natural polyphenolic compound, has been widely studied for its various therapeutic properties. However, its clinical application is constrained by suboptimal pharmacokinetic properties. This study reports on the in silico assessments, comprising molecular docking, molecular dynamics (MD) and density functional theory (DFT) calculations, which revealed the binding interactions and electronic properties of selective curcumin derivatives. Further, we also report the in vitro antiplasmodial effects, haemin binding potential and GSK-3β inhibitory activity of the synthesised curcumin derivatives, to validate the antimalarial efficacy. Ten synthesised compounds from three different types of curcumin derivatives; Knoevenagel condensate, heterocyclic pyrazole and monocarbonyl derivatives, exhibited more effective antiplasmodial activity against both P. falciparum chloroquine-sensitive (CQ-S) 3D7 and chloroquine-resistant (CQ-R) K1 assays, compared to curcumin (EC ₅₀  = 8.32 ± 2.62 µM (3D7) and 30.66 ± 5.44 µM (K1)). We also report, for the first time, the isothermal titration calorimetry (ITC) and in vitro yeast-based assessments to elucidate their multi-targeting potential based on haemin binding activity and immunomodulatory GSK-3β inhibition. Interestingly, some compounds showed multi-targeting potential against haemin and GSK-3β, which also partially influence the effective antimalarial activity. The outcomes from the different analyses incorporating the in vitro assays, ITC assessments and in silico studies, highlighted the promising potential of curcumin derivatives for antimalarial drug research, over the parent curcumin. This study lays the groundwork for further experimental validation and development of curcumin-based compounds as effective and safe antimalarial and anti-inflammatory agents.